In order to reduce systemic toxicities, a promising approach to achieve targeted delivery of cytotoxic drugs to tumor cells is to use antibody-drug conjugates (ADCs) or other types of ligand-drug conjugates as self-guided tumor-targeting drugs. Antibody-drug conjugates, which combine the specificity of monoclonal antibodies and the potency of cytotoxic drugs, have been under intense pursuit for over 30 years. The recent approval of two ADCs, brentuximab vedotin for the treatment of Hodgkin's lymphoma and ado-trastuzumab emtansine for the treatment of metastatic breast cancer, has boosted the research activities in the field to a new level. It has become common for a biotech or pharmaceutical company to have programs in the field of antibody-drug conjugates.
However, even with ADCs, an old problem still exists. It is known that after multiple treatments of cancer patients with chemotherapeutic drugs, the patients may become resistant to such treatment (Szakacs et al. Nat Rev Drug Discov. 2006, 5: 219-34). There are several mechanisms by which tumor cells can become resistant. Among them the multidrug-resistant (MDR) proteins are important membrane pumps that can transport chemotherapeutic agents out of the cells. One of the more prevalent MDR pumps is MDR1. The MDR1, which is also known as P-glycoprotein 1 (PGP1) or ATP-binding cassette sub-family B member 1 (ABCB1), is the most common efflux pump of anticancer drugs, and correlations between MDR1 expression and poor responses to chemotherapy have been demonstrated for many cancer types (Takara et al. Curr Pharm Des 2006, 12: 273-86; Leonard et al. Oncologist 2003, 8: 411-24). Yet, the majority of cytotoxic drugs that have been used in ADCs, such as maytansinoids, dolastatins, calicheamicin, doxorubicin, taxanes, and duocarmycins, are also substrates of the MDR1 transporter, and the activity of many ADCs is poor in MDR1-expressing cells (Takeshita et al. Br J Haematol. 2009, 146, 34-43; Hamann et al. Bioconjug Chem. 2005, 16, 346-53).
MDR1 causes resistance to chemotherapeutic drugs via two mechanisms. First, by effluxing drugs that have diffused into the plasma membrane from extracellular spaces. In such cases, the compounds are prevented from entering the cytoplasm. Second, by effluxing compounds that have entered the cytoplasm to the outside of the cell (Sharom. Pharmacogenomics. 2008, 9, 105-27; Lehne. Curr Drug Targets. 2000, 1, 85-99). Due to that ADCs deliver the cytotoxic drugs to the cytoplasm via antigen-mediated endocytosis, the first type of resistance is prevented (Hamann et al. Bioconjug Chem. 2005, 16, 346-53; Guillemard et al. Oncogene. 2004, 23, 3613-21). However, after the conjugates are processed into small fragments inside the cells, the cytotoxic drugs are still susceptible to the second type of resistance, i.e., the effluxing of drugs from the cytoplasm to extracellular spaces.
For ADCs, the MDR1 not only decreases the potency of cytotoxic drugs, but also decreases the therapeutic index, because once transported to the extracellular spaces by MDR1, the cytotoxic drugs may also cause damage to normal healthy cells of the body. It can significantly compromise the results of the targeted antitumor therapies.
Therefore, even with antibody-drug conjugates, there is still a need to overcome the problem of multidrug resistance. This will help increase the potency and therapeutic index of antibody-drug conjugates, and enable antibody-drug conjugates to achieve the intended goal of targeted antitumor therapy on a much higher level.